CGRP upregulation in dorsal root ganglia and ileal mucosa during Clostridium difficile toxin A-induced enteritis.
We have previously reported that pretreatment of rats with capsaicin (an agent that ablates sensory neurons) or CP-96345 (a substance P receptor antagonist) dramatically inhibits fluid secretion and intestinal inflammation in ileal loops exposed to Clostridium difficile toxin A. The aim of this study was to determine whether calcitonin gene-related peptide (CGRP), a neuropeptide also found in sensory afferent neurons, participates in the enterotoxic effects of toxin A. Administration of toxin A was also found to increase CGRP content in dorsal root ganglia and ileal mucosa 60 min after toxin exposure. Furthermore, immunohistochemical studies demonstrated increased neuronal staining for CGRP 2 h after toxin A treatment. Pretreatment of rats with CGRP-(8-37), a specific CGRP antagonist, before instillation of toxin A into ileal loops significantly inhibited toxin-mediated fluid secretion (by 48%), mannitol permeability (by 83%), and histological damage. We conclude that CGRP, like substance P, contributes to the secretory and inflammatory effects of toxin A via increased production of this peptide from intestinal nerves, including primary sensory afferent neurons.
Keates
A C
AC
Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston 02215, USA.
Castagliuolo
I
I
Qiu
B
B
Nikulasson
S
S
Sengupta
A
A
Pothoulakis
C
C
D000818:Animals; D001427:Bacterial Toxins; D015740:Calcitonin Gene-Related Peptide / Q000096:biosynthesis* / Q000494:pharmacology; D016360:Clostridioides difficile; D004751:Enteritis / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control; D004768:Enterotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity*; D005727:Ganglia, Spinal / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D007082:Ileum; D007249:Inflammation; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D001427:Bacterial Toxins; D004768:Enterotoxins; D010446:Peptide Fragments; C041348:tcdA protein, Clostridium difficile; C058636:calcitonin gene-related peptide (8-37); D015740:Calcitonin Gene-Related Peptide